Geographic atrophy (GA) is a severe form of age-related macular degeneration (AMD) and a major cause of vision loss among individuals older than 55 years in the United States. Currently, no effective treatment exists for GA, and its cause, and even the primary cell type affected, remains poorly understood. This gap in understanding represents a critical barrier in the development of new treatments. This project will address this barrier by focusing on identification of the primary site of cell damage in GA. The goal of this project is to capitalize on recent innovations in high resolution retinal imaging o test our central hypothesis that the sequence of cellular loss in the progression of geographic atrophy begins with loss of rod photoreceptors, followed by cones, and finally retinal pigment epithelial (RPE) cells. Advances in retinal imaging with fluorescence adaptive optics scanning laser ophthalmoscopy (FAOSLO) have for the first time enabled the identification of individual cones, rods, and RPE cells simultaneously in living human patients. The impact of this capability is the potential to determine the temporal sequence of retinal disease at a microscopic scale. Aim1. Test the hypothesis that photoreceptor cell loss precedes RPE cell loss in GA progression. We will microdissect the temporal sequence of cellular damage in GA in both cell layers using AO imaging of the functional zone surrounding GA lesions to monitor the wave of progression in the photoreceptor and RPE layers simultaneously. Aim 2. Test the hypothesis that hyperautofluorescence in the junctional zone surrounding GA lesions is preceded by loss of photoreceptors. Aim 3. Test the hypothesis that loss of rod photoreceptors in GA is preceded by visual cycle disruption in the rod outer segments. Expected outcomes of the proposed study include determination of the primary cell type affected in the GA form of AMD. Validation of the overall hypothesis could redirect efforts at developing new treatments to the preservation of rod photoreceptor cell health and provide a finer outcome measure for future clinical trials. PUBLIC HEALTH RELEVANCE: Geographic atrophy (GA), a severe form of age-related macular degeneration (AMD), a major cause of vision loss among individuals older than 55 years in the United States, has no effective treatment and its cause is unknown. The goal of this project is to use the fluorescence adaptive optics scanning laser ophthalmoscope (FAOSLO), a novel optical imaging technology which can view single retinal cells in a living patient's eye, in order to determine which type of retinal cells are the first to be damaged by GA. Identifying the earliest changes in GA would help focus scientific efforts at developing new treatments for GA and would provide a valuable method to test the efficacy of potential therapies.